Apoptosis is a fundamental process in the development and maintenance of multicellular organisms and its regulation is commonly disrupted in human cancers. In vitro and in vivo, effective treatment of cancer with radiotherapy or anticancer drugs (or both) is frequently associated with increased markers of apoptosis. However, clinical resistance to treatment is common in many tumours, particularly with increasing lines of therapy. Diminished ability to undergo apoptosis might cause extensive therapeutic cross-resistance in cancer cells. With increased understanding of the regulatory and effector molecules of apoptosis new drugs have been developed that might manipulate the apoptotic balance in cancer cells in favour of cell death. This Review summarises the rationale for direct manipulation of various elements of apoptosis and describes agents that are currently under investigation in early-phase clinical trials in many different cancer types.